A Rare Yet Serious Condition: Neuroleptic Malignant Syndrome (NMS) Ravi Parmar 2017/2018 Island Health Pharmacy Resident Psychiatry Rotation Oct 2017

Objectives To define NMS and outline a typical clinical presentation To discuss the suspected pathophysiology of NMS and medications that are associated with this condition To outline different treatment options for NMS

Definition NMS is a potentially lethal neurological emergency known to be an adverse reaction to neuroleptic medications that can occur anytime during treatment (e.g. from 1-3 days after initiation or dose change, or after being stable on a dose for years) Neuroleptic = a drug that depresses nerve functions Modi et al. Neurocrit Care. 2016

Presentation https://www.slideshare.net/alyaqdhan/nms-neuroleptic-malignant-syndrome - Typically evolves over 1-3 days. Each feature is present in 97-100 % of patients UpToDate: Neuroleptic Malignant Syndrome

Diagnostic Criteria DSM V Exposure to dopamine antagonist, or dopamine agonist withdrawal, within past 72 hours Hyperthermia (>100.4°F or >38.0°C on at least 2 occasions, measured orally) Rigidity Mental status alteration (reduced or fluctuating level of consciousness) CK elevation (at least 4 times upper limit of normal) Sympathetic nervous system lability, defined as at least 2 of the following: Blood pressure elevation (systolic or diastolic ≥25% above baseline) Blood pressure fluctuation (≥20 mmHg diastolic change or ≥25 mmHg systolic change within 24 hours) Diaphoresis Urinary incontinence Hypermetabolism, defined as heart rate increase (≥25% above baseline) and respiratory rate increase (≥50% above baseline) Negative work-up for infectious, toxic, metabolic, and neurological causes. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th edition (DSM-5). Washington, DC: American Psychiatric Publishing; 2013. DSM V 2013

Atypical Cases Milder or atypical cases may rarely present in a manner in which all 4 cardinal features of the tetrad may not occur These cases are thought to occur more often with low potency agents (e.g. atypical antipsychotics) or in these diagnosed early on Rigidity may be milder or absent, and although fever is thought to be an essential feature, cases have been reported where it was not present Diagnosis should be considered when any two of the tetrad of symptoms are present in a patient who is on a potentially contributing agent UpToDate: Neuroleptic Malignant Syndrome

Differential https://www.slideshare.net/angelajackson1/neuroleptic-malignant-syndrome-2

Suggested Workup Requested Test Why Requested Complete Blood Count To exclude leukocytosis and all kinds of hemolysis and its consequences Blood cultures To exclude possibilities of septic shock (coma) LFTs To exclude hepatic failure for one reason or another BUN and creatinine levels To exclude renal failure Calcium, phosphate, potassium, and sodium levels To exclude electrolyte imbalances and hemolysis CK level To exclude or prove rhabdomyolysis or other myocytes type necrosis Serum iron level Because of rhabdomyolysis and other hemolytic pathologies Urine myoglobin level To exclude myoglobinuria Arterial blood gas analysis To exclude respiratory failure and metabolic acidosis Coagulation studies To exclude hepatic failure and disseminated intravascular coagulopathy Serum and urine toxicologic screening To exclude ASA, cocaine and amphetamines poisoning Oruch et al. Neuropsychiatric Disease and Treatment. 2017

Lab Data in Typical Case of NMS Parameters Changes Enzymes and abnormal protein in plasma LDH Increased CK Increased in (50-100% of cases) ALP Myoglobin Myoglobinemia Serum electrolytes and proteolysis remnants Phosphate Hyperphosphatemia Potassium Hyperkalemia Calcium Hypocalcemia Magnesium Hypomagnesemia Sodium Hypo or hypernatremia Oruch et al. Neuropsychiatric Disease and Treatment. 2017

Lab Data in Typical Case of NMS Parameters Changes Elements of blood Leukocytes Leukocytosis (70-80% of cases) Blood platelets (thrombocytes) Thrombocytosis (thrombocytopenia – rarely) Urine Protein Proteinuria (increased protein) Myoglobin Myoglobinuria (increased myoglobin) pH (blood gas analysis) Decreased (metabolic acidosis) Oruch et al. Neuropsychiatric Disease and Treatment. 2017

Iron Deficiency in NMS Reduced serum iron may reduce the number of functional dopamine receptors, thereby making patients more vulnerable to even seemingly low dose antipsychotics In patients with suspected iron deficiency anemia with the requirement of antipsychotic therapy, it would be wise to initiate correction of the iron deficiency and give lower doses of antipsychotics whilst being vigilant of signs of NMS Patil et al. Int J Appl Basic Med Res. 2014

Epidemiology The incidence of NMS ranges from 0.02 to 3% for patients taking neuroleptic agents It is seen more often in young adults, however can occur at any age Males are approximately 50% more likely to be diagnosed at any age (possibly due to higher muscle mass, higher sweat gland output, and increased antipsychotic exposure) The Canada Vigilance Reaction Outline (CVARO) database estimates 442 reported cases of NMS between Jan 1965 and Sep 2012 Gurrera RJ. Acta Psychiatr Scand. 2017 UpToDate: Neuroleptic Malignant Syndrome

Associated Medications It is most often associated with typical high potency neuroleptics (e.g. haloperidol, fluphenazine) However, every class of neuroleptic has been implicated, including low potency (e.g. chlorpromazine) and newer atypical antipsychotics (e.g. clozapine, risperidone, olanzapine) as well as antiemetic drugs (e.g. metoclopramide, promethazine) UpToDate: Neuroleptic Malignant Syndrome

Associated Medications Gautam Bhandari Neuroleptic Malignant Syndrome http://www.apiindia.org/medicine_update_2013/chap118.pdf

Pathophysiology The pathophysiology of NMS is not entirely understood, but it is believed to occur secondary to an acute imbalance or dysregulation of CNS neurotransmitters The associated medications clearly implicate dopamine systems, but other neurotransmitter systems (GABA, epinephrine, serotonin, acetylcholine) appear to be involved as well UpToDate: Neuroleptic Malignant Syndrome

Pathophysiology

Risk Factors Category Variable Pharmacological Treatment Initial phases of treatment, or change of dosage Any antipsychotic treatment (particularly high dose or high potency antipsychotic) Parenteral administration (IV or IM) Polypharmacy Other compounds: antidepressants, mood stabilizers (especially lithium), antiparkinsonians Environmental Factors Physical restraint Dehydration High temperature Demographics Age Multiple co-morbidites Genetic Liability Previous NMS Family hx. of catatonic syndrome Muscle channelopathy Tse et al. Current Neuropharmacology. 2015

Primary Prevention Use the lowest effective dose of antipsychotic medications Avoid rapid escalation of antipsychotics if possible Avoid abrupt withdrawal of dopaminergic agents Treat agitation early, and use alternatives to antipsychotics when possible Avoid dehydration Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007; 164: 870-876 Strawn et al. Am J Psychiatry. 2007

Discontinue offending agent Treatment Pharmacotherapy or ECT Discontinue offending agent Supportive Therapy UpToDate: Neuroleptic Malignant Syndrome

Discontinue Offending Agent The single most critical strategy in the therapeutic management of this potentially lethal condition is to discontinue the suspected pharmacological compound It is not necessary to delay discontinuation in order to seek confirmatory evidence. One should immediately discontinue the potentially harmful compound upon suspicion of NMS Tse et al. Current Neuropharmacology. 2015

Supportive Therapy The need for supportive care is NMS is essential, as complications may include: Dehydration Electrolyte imbalance Acute renal failure associated with rhabdomyolysis Cardiac arrhythmias including torsades de pointes and cardiac arrest Myocardial infarction Cardiomyopathy Respiratory failure from chest wall rigidity, aspiration pneumonia, pulmonary embolism Deep vein thrombophlebitis Thrombocytopenia Disseminated intravascular coagulation Deep vein thrombosis Seizures from hyperthermia and metabolic derangements Hepatic failure Sepsis UpToDate: Neuroleptic Malignant Syndrome

Supportive Therapy Cooling blankets and antipyretics (controversial – hyperthermia likely result of anticholinergic and dopaminergic effects of antipsychotics versus prostaglandins) may both be used to reduce fever Fluid resuscitation and electrolyte correction may be required Maintaining a slightly alkalotic pH may prevent rhabdomyolysis and AKI For labile hypertension, calcium channel blockers have been suggested because they may also reverse toxicity at the musculoskeletal level If immobilized from rigidity, DVT prophylaxis should be initiated Patients with dysphagia may need a NG tube for administration of fluids, nutrition, and medications In severe cases, intubation may be needed in patients with muscle rigidity extending to their airway There have been reports of NMS being successfully treated with supportive therapy alone, however in cases of severe rigidity and hyperthermia, pharmacotherapy is generally required for symptom resolution Pileggi et al. Annals of Pharmacotherapy. 2016

Pharmacotherapy Dantrolene Bromocriptine Benzodiazepines Amantadine There is limited evidence on whether pharmacological treatments truly reduce symptoms or improve recovery, but options include: Dantrolene Bromocriptine Benzodiazepines Amantadine Other agents with anecdotal success include levodopa, apomorphine, and carbamazepine Pileggi et al. Annals of Pharmacotherapy. 2016 UpToDate: Neuroleptic Malignant Syndrome

Dantrolene Direct skeletal muscle relaxant that disrupts excitation-contraction coupling by blocking calcium efflux from the sarcoplasmic reticulum Dosage: Intravenously – 1 to 2.5 mg/kg initially; if rapid resolution of hyperthermia and rigidity is observed, may follow with 1 mg/kg q6h up to a max cumulative dose of 10 mg/kg/day, then switch to oral dosage It is the drug of choice for treatment of malignant hyperthermia, and since 1981 has been routinely used for NMS treatment in more severe cases although efficacy data is controversial There is an associated risk of hepatotoxicity and LFTs should be done prior to administration The dose of dantrolene may be weaned over several days to avoid recurrence of NMS Based on an analysis of 271 case reports, dantrolene in combination with other therapies (e.g. bromocriptine) may be preferred over monotherapy due to lower mortality and longer complete time of remission Tse et al. Current Neuropharmacology. 2015 Lexicomp: Dantrolene Pileggi et al. Annals of Pharmacotherapy. 2016

Bromocriptine Ergot derivative with potent agonist activity in the postsynaptic D2 receptor Used primarily in the treatment of Parkinson's Disease, however in NMS it may counteract dopamine blockade attributed to antipsychotics Dosage: Oral – 2.5 mg (orally or via gastric tube) every 8-12 hours, increased to a maximum of 45 mg daily, if needed; continue therapy until NMS is controlled, then taper slowly Because of its ability to cause hypotension, initial dosing tends to begin in the lower end of the dosing range, and upward titration as tolerated is done over several days Tse et al. Current Neuropharmacology. 2015 Lexicomp: Bromocriptine Pileggi et al. Annals of Pharmacotherapy. 2016

Benzodiazepines Work through reversal of the hypofunctioning GABAergic system that contributes to NMS symptoms Of the benzodiazepines, literature supports use of lorazepam, diazepam, and clonazepam as treatment for NMS Dosages used varied between studies (e.g. lorazepam 1-2 mg IM or IV q4-6h, diazepam 10 mg IV q8h, clonazepam 1 mg q3h) Can be administered by several different routes (IV, IM, oral, buccal, intranasal, and rectal), so the route and dose can be individualized based on clinical scenario Patients should be monitored for signs of respiratory depression and/or delirium Pileggi et al. Annals of Pharmacotherapy. 2016

Amantadine Though the mechanism through which it works is not clearly understood, it is likely a result of both direct increase in dopamine release and reduction in reuptake It also has anticholinergic-like activity that could shift D2 receptors to high affinity states and functions as a weak NMDA receptor antagonist and has shown to improve dyskinesias associated with levodopa Dosage: Oral – 100 mg orally or via gastric tube and is titrated upward as needed to a maximum dosage of 200 mg q12h Generally used as adjunctive treatment in NMS for moderate to severe cases Pileggi et al. Annals of Pharmacotherapy. 2016 UpToDate: Neuroleptic Malignant Syndrome

ECT When multiple medications have failed, ECT has been used successfully It has also been suggested that patients with only a partial response to pharmacotherapy could receive a course of ECT to ameliorate the remaining symptoms It is unclear how this method improves symptoms, but it has been shown to be effective in a variety of other refractory psychological illnesses Safety concerns include cardiovascular complications, status epilepticus, uncontrolled spontaneous seizures, and aspiration pneumonia as reported through case reports of ECT in NMS Pileggi et al. Annals of Pharmacotherapy. 2016 UpToDate: Neuroleptic Malignant Syndrome

Treatment Algorithm Pileggi et al. Annals of Pharmacotherapy. 2016

Prognosis Mainly dependent on early diagnosis and active intervention without delay Most cases resolve within two weeks. Reported mean recovery times are 7 to 11 days (longer if LAIs implicated) Although the majority of cases can be successfully managed, it is important to be aware that ~ 10% of cases can be fatal, regardless of early diagnosis and treatment Oruch et al. Neuropsychiatric Disease and Treatment. 2017

Restarting Neuroleptics The population most at risk for developing NMS from antipsychotic use is generally the same population that needs this therapy the most for their underlying condition Reported rates of recurrence of NMS vary and may be as high as 30% Following resolution of NMS, the patient should be evaluated for re-challenge with neuroleptics or for management with an alternative agent If antipsychotic therapy needs to be continued, an agent that has low D2 affinity (e.g. quetiapine) should be selected and started at a low initial dose Acute recurrence of NMS may depend more on the time between NMS resolution and re-challenge than on the antipsychotic chosen Analysis of more than 40 re-challenges have suggested success if the washout period from symptom resolution is at least 5 days (another report suggested at least 14 days) Careful monitoring and slow titration are required regardless of the period ECT may be a possible treatment option for the underlying illness if patients refuse re-challenge or have severe sequelae Pileggi et al. Annals of Pharmacotherapy. 2016

Summary NMS is a potentially lethal neurological emergency known to be an adverse reaction to neuroleptic medications Believed to occur secondary to an acute imbalance or dysregulation of CNS neurotransmitters (especially dopamine systems) Cardinal symptoms include: fever, muscle rigidity, altered mental status, and autonomic instability The most important treatment option is stopping suspected contributing medications. Supportive measures are also vital for the numerous potential complications of NMS Other pharmacologic options include: dantrolene, bromocriptine, benzodiazepines, amantadine, and ECT Prognosis mainly depends on early diagnosis and active intervention without delay